US7268150B2 - 2-cyano-4-fluoropyrrolidine derivative or its salt - Google Patents

2-cyano-4-fluoropyrrolidine derivative or its salt Download PDF

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US7268150B2
US7268150B2 US10/492,347 US49234704A US7268150B2 US 7268150 B2 US7268150 B2 US 7268150B2 US 49234704 A US49234704 A US 49234704A US 7268150 B2 US7268150 B2 US 7268150B2
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fab
fum
group
fluoro
amino
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US20050176771A1 (en
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Masahiko Hayakawa
Kenji Negoro
Satoshi Miyamoto
Takayuki Suzuki
Tatsuya Maruyama
Ryosuke Nakano
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Astellas Pharma Inc
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Yamanouchi Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system

Definitions

  • Non-patent reference 2 Nauck M. A., Diabetologia, 1986, Vol. 29, pp. 46-52.
  • Non-patent reference 3 Drucker D. J., Diabetes, 1998, Vol. 47, pp. 159-169
  • A is a group of formula (II) and B is carbonyl.
  • Aryl means a C 6-14 monocyclic to tricyclic, aromatic monovalent group consisting of carbon atoms, for example, concretely including phenyl and naphthyl, etc. Preferably, it is phenyl.
  • “Aromatic hetero ring” means a monocyclic to tricyclic aromatic monovalent group having at least one hetero atom selected from the group consisting of nitrogen, oxygen and sulfur atoms, for example, concretely including furanyl, thienyl, pyrrolyl, pyridyl, oxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, tetrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, isoxazolyl, triazolyl, benzofuranyl, benzothienyl, benzothiadiazolyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzotriazolyl, indolyl, isoindolyl, quinazolyl, quinolyl, isoquinolyl, quinoxayl, imidazopyridinyl and imidazo
  • the substituent to bond to the carbon atom includes a substituent group X, —OH, —O—X, halogen, —CO—X, —COO—X, —SO 2 —X and —CONRR′.
  • it is lower alkyl or aryl, each of which is optionally substituted with one or more group selected from the group consisting of —OH, —O-lower alkyl, —O-aryl, halogen, cyano and nitro, more preferably lower alkyl optionally substituted with a substituent selected from —OH and fluorine.
  • “Lower alkenyl” means a C 2-6 alkenyl, for example, concretely including vinyl, allyl, 1-propenyl, 1-butenyl, 2-butenyl and 3-butenyl.
  • the compounds of the invention may form acid-addition salts. Depending on the type of the substituent therein, they may form salts with bases.
  • the salts include acid-addition salts with mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, or with organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid; salts with acidic amino acids such as aspartic acid, glutamic acid, or with inorganic bases such as sodium, potassium, magnesium, calcium, aluminium, or with organic bases such as methylamine, ethylamine, ethanolamine; or with basic amino acids such as lysine, orni
  • the compounds of the invention further include hydrates, various pharmaceutically acceptable solvates, and polymorphic crystals.
  • the invention should not be limited to the compounds described in Examples given hereinunder, and include all derivatives of formula (I) and their pharmaceutically acceptable salts.
  • the compound of the invention and its pharmaceutically acceptable salt can be produced through application of various known synthesis processes by utilizing the characteristic based on the basic skeleton thereof or kinds of the substituents.
  • a functional group i.e., a group that can be readily converted into the functional group in a state of the starting material or intermediates.
  • the protective group is removed, thereby enabling to obtain the desired compound.
  • a functional group include a hydroxyl group, a carboxyl group and an amino group.
  • the protective group thereof include the protective groups as described in Greene and Wuts, Protective Groups in Organic Synthesis ( third edition ), and these may be properly used depending on the reaction conditions.
  • A has the same meaning as above; and X represents a leaving group such as halogen or sulfonyloxy group.
  • the method comprises alkylation of a compound (II) with an amine (III) of a general formula, A—NH 2 to give the compound (I) of the invention.
  • the reaction may be effected in the absence or presence of a solvent.
  • the solvent may be any of aromatic hydrocarbons such as toluene, xylene; ketones such as methyl ethyl ketone, acetone; ethers such as dioxane, tetrahydrofuran, diglyme; alcohols such as methanol, ethanol, isopropanol; chloroform, methylene chloride, acetonitrile, dimethylformamide, dimethylsulfoxide, water; and their mixed solvents.
  • a suitable solvent may be selected for the reaction.
  • Adding a base to the reaction is preferred for smoothly effecting the reaction.
  • the base are alkali carbonates such as sodium carbonate, potassium carbonate; alkali hydrogencarbonates such as sodium hydrogencarbonate, potassium hydrogencarbonate; and organic amines such as triethylamine, diisopropylethylamine, pyridine.
  • the compounds of the invention may be isolated and purified as they are in the form of free compounds, or after salted into their salts in an ordinary manner.
  • the isolation and purification may be effected in any ordinary chemical operation such as extraction, concentration, distillation, crystallization, filtration, recrystallization, various modes of chromatography, etc.
  • the compounds of the invention are useful for remedy and/or prevention of insulin-dependent diabetes (type 1 diabetes), especially non insulin-dependent diabetes (type 2 diabetes), insulin-resistant disorders, and obesity.
  • mice Male ICR mice (Nippon SLC) were grouped into a test group and a control group of 5 subjects each.
  • a test compound (10 mg/kg) was dissolved in purified water, and orally administered. Purified water alone was orally administered to the mice of the control group.
  • One half, 6, and 12 hours after the administration the blood was collected from each mouse through the orbital venous plexus thereof. The collected blood was immediately centrifuged to isolate the plasma, and the DPP-IV activity of the plasma was measured.
  • the process of plasma DPP-IV activity determination was as follows: The reaction was performed in a 96-well plate. 5 ⁇ l of the collected plasma was added to an aqueous solution (95 ⁇ l/well) comprises 25 mM Tris-HCl, 140 mM sodium chloride, 10 mM potassium chloride, 1% bovine serum albumin, and 0.01 mM Gly-Pro-AMC (Bachem), and incubated at room temperature for 20 minutes. The fluorescence intensity (excitation 355 nm/emission 460 nm) of each well was measured (ARVO, Perkin Elmer).
  • Test compound (10 mg/kg) was dissolved in purified water, and orally administered. Purified water alone was orally administered to the rats of the control group. One half, 6, and 12 hours after the administration, the blood was collected from each rat through the tail vein thereof. The collected blood was immediately centrifuged to isolate the plasma, and the DPP-IV activity of the plasma was measured according to the same process as in the dipeptidyl peptidase-IV (DPP-IV) inhibiting activity duration test shown in (2).
  • DPP-IV dipeptidyl peptidase-IV
  • the fluorescent intensity of the well, to which was added the plasma collected from the control group was 100%. Based on it, the DPP-IV activity of the plasma collected from the test compound-administered rats was calculated, and the activity difference between the control group and the test group was obtained. This indicated the inhibition in the test group. The result is given in Table 3.
  • comparative compound 1 represents Example 4-9 described in patent reference 5
  • comparative compound 2 represents Example 4-17 described in patent reference 5
  • comparative compound 3 represents Example 33 described in patent reference 7; each patent reference is mentioned above.
  • the structure of comparative compounds 1-3 will be shown below.
  • a suspension of 1.0 g of tert-butyl piperidin-4-ylcarbamate hydrochloride and 0.6 ml of triethylamine in 15 ml of methylene chloride was added to a solution of 418 mg of triphosgene in 10 ml of methylene chloride under cooling with ice-water bath.
  • the reaction mixture was stirred for 2 hours with ice cooling, and then a solution of 358 mg of piperidine and 0.6 ml of triethylamine in 5 ml of methylene chloride was added thereto and stirred at room temperature for 15 hours.
  • Aqueous 10% citric acid solution was added to the reaction mixture, and this was extracted with EtOAc.
  • Salt salt (HCl: hydrochloride, fum: fumarate, not described: free compound)

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Diabetes (AREA)
  • Animal Behavior & Ethology (AREA)
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  • Child & Adolescent Psychology (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
US10/492,347 2002-07-23 2003-07-18 2-cyano-4-fluoropyrrolidine derivative or its salt Expired - Fee Related US7268150B2 (en)

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JP2002213654 2002-07-23
JP2002-213654 2002-07-23
JP2002264450 2002-09-10
JP2002-264450 2002-09-10
PCT/JP2003/009179 WO2004009544A1 (ja) 2002-07-23 2003-07-18 2-シアノ−４−フルオロピロリジン誘導体又はその塩

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EP (1) EP1541551A4 (no)
JP (1) JP3778207B2 (no)
KR (1) KR100633844B1 (no)
CN (1) CN1312127C (no)
AR (1) AR040653A1 (no)
AU (1) AU2003281625A1 (no)
BR (1) BR0312844A (no)
CA (1) CA2493339A1 (no)
IL (1) IL166239A0 (no)
MX (1) MXPA05000896A (no)
NO (1) NO20050945L (no)
NZ (1) NZ537658A (no)
PL (1) PL374854A1 (no)
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TW (1) TW200401635A (no)
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Cited By (11)

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US20090048454A1 (en) * 2006-03-08 2009-02-19 Yoshikazu Asahina Process for Producing Aminoacetyl Pyrrolidine Carbonitrile Derivative and Intermediate for Production Thereof
US20090105249A1 (en) * 2004-10-14 2009-04-23 Euro-Celtique S.A. 4-phenylsulfonamidopiperidines as calcium channel blockers
US20090239910A1 (en) * 2006-03-29 2009-09-24 Zhengning Chen Benzenesulfonamide Compounds and Their Use
US20090306136A1 (en) * 2006-04-13 2009-12-10 Akira Matsumura Benzenesulfonamide Compounds and the Use Thereof
US20100022595A1 (en) * 2006-04-13 2010-01-28 Purdue Pharma L.P. Benzenesulfonamide Compounds and Their Use as Blockers of Calcium Channels
US20100291020A1 (en) * 2007-09-21 2010-11-18 Lupin Limited Novel compounds as dipeptidyl peptidase iv (dpp iv) inhibitors
US20100311792A1 (en) * 2007-09-28 2010-12-09 Bin Shao Benzenesulfonamide Compounds and the Use Thereof
US20110137070A1 (en) * 2008-08-07 2011-06-09 Tomohiro Akeboshi Process for production of bicyclo[2.2.2]octylamine derivative
US20110152342A1 (en) * 2008-08-14 2011-06-23 Hiroshi Uchida Stabilized pharmaceutical composition
US8399486B2 (en) 2007-04-09 2013-03-19 Purdue Pharma L.P. Benzenesulfonyl compounds and the use thereof
US8748457B2 (en) 2009-06-18 2014-06-10 Lupin Limited 2-amino-2- [8-(dimethyl carbamoyl)- 8-aza- bicyclo [3.2.1] oct-3-yl]-exo- ethanoyl derivatives as potent DPP-IV inhibitors

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JPWO2008114857A1 (ja) * 2007-03-22 2010-07-08 杏林製薬株式会社 アミノアセチルピロリジンカルボニトリル誘導体の製造方法
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